Certain 6a,10a-trans-hexahydrodibenzopyranones have recently been found useful in the treatment of anxiety, analgesia, and depression; see U.S. Pat. Nos. 3,928,598, 3,944,673, and 3,953,603 respectively. Archer et al., in U.S. Pat. No. 4,087,545, described the use of such compounds in the prevention and treatment of emesis and nausea in mammals. One compound within this class, namely dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a7,8,10,10a-hexa hydro-9H-dibenzo[b,d]pyran-9-one, is now known generically as nabilone and is available in some countries as an antiemetic agent to be used in cancer chemotherapy, wherein cancer drugs often cause severe nausea.
The initial syntheses of hexahydrodibenzopyranones were quite lengthy and expensive, and generally led to hard to separate mixtures; see Fahrenholtz et al., J. Am. Chem. Soc., 88, 2079 (1966); 89, 5934 (1967). These authors reported a synthesis that gave both the 6a,10a-cis isomers and 6a,10a-trans isomers. The cis isomers demonstrated little if any pharmacological activity, and were thus not claimed to have a utility, U.S. Pat. No. 3,507,885. Blanchard et al., in U.S. Pat. No. 4,054,582, disclosed a method for quantitatively converting the 6a,10a-cis isomers to the pharmacologically active 6a10a-trans isomers. Day et al., in U.S. Pat. No. 4,148,809, disclosed a convenient one step synthesis of the 6a,10a-cis compounds required in the Blanchard et al. process. This one step synthesis comprises condensing a 5-substituted resorcinol with a cyclohexene carbinol, namely a 1-alkoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene, in the presence of a catalyst such as stannic chloride. Extensions of this process are described in U.S. Pat. No. 4,054,581 and 4,171,315.
I have now discovered that reaction of a protected resorcinol, for example a 3-alkoxy-5-substituted phenol, with a cyclohexene carbinol in the presence of a catalyst such as stannic chloride produces a 6a,10a-trans-hexahydrodibenzopyranone directly. An object of this invention thus is to provide a convenient one step synthesis of such 6a,10a-trans compounds.